EP0518722B1 - Dithian substituierte Retinoide, ihre Verwendung, Verfahren zu ihrer Herstellung, diese enthaltende kosmetische und pharmazeutische Zusammensetzungen und ihre therapeutische Verwendung - Google Patents

Dithian substituierte Retinoide, ihre Verwendung, Verfahren zu ihrer Herstellung, diese enthaltende kosmetische und pharmazeutische Zusammensetzungen und ihre therapeutische Verwendung Download PDF

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Publication number
EP0518722B1
EP0518722B1 EP92401487A EP92401487A EP0518722B1 EP 0518722 B1 EP0518722 B1 EP 0518722B1 EP 92401487 A EP92401487 A EP 92401487A EP 92401487 A EP92401487 A EP 92401487A EP 0518722 B1 EP0518722 B1 EP 0518722B1
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Prior art keywords
est
formula
solution
par
hexane
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EP92401487A
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French (fr)
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EP0518722A1 (de
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Guy Solladie
Valérie Berl
Jean Maignan
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LOreal SA
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LOreal SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4986—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with sulfur as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/14—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by doubly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to retinoid derivatives substituted by a dithian cycle, their preparation process, their use as a starting point for hydrolysis and their use in human and veterinary medicine and in cosmetics, in the form of compositions.
  • the retinoid family includes natural compounds, in particular vitamin A or retinol, retinal and retinoic acid, and a certain number of derivatives obtained by synthesis.
  • Retinoids are, in known manner, compounds used for the cosmetic or pharmaceutical treatment of skin conditions associated with disturbances of epidermal differentiation such as psoriasis or acne.
  • the use of retinol and its derivatives, for example, is described in EP-A-0 391 033. It is very important to master the stereochemistry of the various reactions for the synthesis of retinoids so as to obtain retinoids having a determined stereospecificity and not retinoids in the form of a mixture of different stereoisomers. Indeed, the mode of use of retinoids may not be the same depending on their stereochemical form. For example, clinically, all-trans retinoic acid is used in topical form and 13-cis retinoic acid is used in systemic form.
  • the subject of the present invention is sulfur-containing retinoic compounds, prepared in a determined stereochemical form: all-trans or 13-cis, capable, by hydrolysis, of transforming into retinal or retinoic acid having the same stereospecific form, and a manufacturing process. making it possible to prepare these compounds in a stereochemical form determined from a starting compound, called "synthon", of corresponding stereospecific form.
  • the present invention therefore relates to a stereospecific retinoic compound of formula: formula in which R is H or a C 1 -C 4 thioalkyl radical.
  • the position -trans of the dithian cycle is represented by putting the axis of symmetry of this oblique cycle upwards and the position -cis by orienting said axis downwards.
  • this axis is represented horizontal, the formula designates the stereospecific form -cis or the stereospecific form -trans without distinction.
  • the present invention relates more particularly to the all-trans retinal thioacetal of formula: the thioacetal of retinal 13-cis of formula: and the retinoic acid orthothioester-trans of formula:
  • the compounds of formula (I) give the retinal or retinoic acid in the stereospecific form corresponding to that of the hydrolyzed compound.
  • the compounds of formula (II) and (III) give respectively the all-trans retinal and the 13-cis retinal and the compound of formula (IV) of retinoic acid in -trans form.
  • a subject of the invention is therefore also the use of the compounds of formula (I) for obtaining by hydrolysis a retinal or a stereospecific retinoic acid.
  • the compounds of formula (I) are prepared from diols having the corresponding stereospecificity of formula: where R has the same meaning as above, by reduction using “low valence” titanium, so removing the two hydroxyl groups and obtaining a fourth double bond.
  • “Low valence” titanium is obtained, in a known manner, by reduction of TiCl 3 or TiCl 4 with a metal such as magnesium, potassium, sodium, lithium, the zinc-copper couple or a lithium hydride and aluminum.
  • a mixture of TiCl 3 and LiAlH 4 is used .
  • FR-A-2 615 509 there is described a process for the reduction of a triene diol to a retinoic compound comprising four conjugated ethylenic double bonds.
  • the reduction using “low valence” titanium made it possible to preserve the stereospecificity.
  • an all-trans retinoid is obtained.
  • the diols of formula (V) are prepared by reaction of a stereospecific dithiane-propenal of formula: where R has the same meaning as above, with ethynyl- ⁇ -ionol of formula: by Grignard reaction in the presence of a organomagnesium, so as to obtain the acetylene compound of formula: where R has the same meaning as above, then by hydrogenation of the compound of formula (VIII) to obtain the diol of formula (V).
  • the hydrogenation is preferably carried out using lithium aluminum hydride.
  • a subject of the invention is therefore also the process for preparing the compounds of formula (I) from the compounds of formula (VI) by the various steps defined above.
  • dithiane-propenals of formula (VI) used are known. This is the case, in particular, for dithianepropenal-trans of formula: which is described in T.SAKO, K. HANAYAMA, T. FUJISAWA Tetrahedron Letters, 29, 2197 (1988) and K. RUSTEMEIER, E. BREITMAIER Chem. Ber, 115, 3898 (1982).
  • dithiane-propenals are new products, the synthesis of which is described in detail in the patent application (EP-A-0 518 724) which is filed on the same day. that this request by the plaintiff; this is, for example, the case of the dithianepropenal-cis of formula: and the orthothioester-trans of formula:
  • the new compounds of formula (I) also find application in the topical and systemic treatment of dermatological conditions linked to a disorder of keratinization (differentiation-proliferation) and of dermatological or other conditions, with inflammatory and / or immunoallergic components and in degenerative diseases of connective tissue, and have anti-tumor activity.
  • these compounds can be used in the treatment of atopy, whether cutaneous or respiratory, and rheumatoid psoriasis. They also find an application in the ophthalmological field, in particular in the treatment of corneopathies.
  • the present invention therefore also relates to a pharmaceutical composition containing, in a vehicle suitable for administration by the enteral, parenteral, topical or ocular route, at least one compound of formula (I) as defined above, as well as the use of such a composition for the treatment of the aforementioned conditions.
  • the compounds of formula (I) are generally administered at a daily dose of approximately 0.01 mg to approximately 100 mg / kg of body weight in 1 to 3 doses.
  • the pharmaceutical compositions of the invention can be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles allowing controlled release.
  • compositions of the invention may be in the form of solutions or suspensions for infusion or for injection.
  • compositions of the invention are intended for the treatment of the skin and mucous membranes and are in the form of ointments, creams, milks, ointments, powders, soaked pads, solutions, gels, sprays, lotions or suspensions; they can also be in the form of microspheres or nanospheres or of lipid or polymeric vesicles or of polymeric "patches" or of hydrogels allowing controlled release; they can be presented either in anhydrous form, or in aqueous form, according to the clinical indication.
  • the pharmaceutical compositions of the invention are mainly eye drops.
  • compositions of the invention contain, at a concentration, preferably between 0.0001 and approximately 5% by weight relative to the total weight of the composition, at least one compound of formula (I) as defined above above.
  • the compounds of formula (I) also find application in the cosmetic field, in particular in body and hair hygiene and in particular for the treatment of acne-prone skin, for hair regrowth, anti-hair loss, for combating against the oily appearance of the skin or hair, in protection against the harmful effects of the sun or in the treatment of physiologically dry skin.
  • the present invention therefore finally relates to a cosmetic composition containing, in an appropriate cosmetic vehicle, at least one compound of formula (I), this composition being in particular in the form of a cream, a milk, a lotion , a gel, microspheres or nanospheres or lipid vesicles or polymeric, soap or shampoo.
  • concentration of compound (s) of formula (I) in these cosmetic compositions is preferably between 0.0001 and approximately 3% by weight relative to the total weight of the composition.
  • compositions according to the invention may contain inert additives or pharmacodynamically or cosmetically active additives.
  • the compound (Z 15 ) is prepared as described in Example 1.
  • This gel is applied to dermatosis or acne-prone skin 1 to 3 times a day. After 6 to 12 weeks of treatment at a rate of 2 to 10 mg per cm 2 of treated skin and per application, there is a significant improvement.
  • the capsules used are made of gelatin, titanium oxide and a preservative.
  • An adult individual is given 1 to 3 capsules per day in the treatment of psoriasis. After 30 days of treatment at a rate of 1 mg per kg of subject treated per day, there is a significant improvement.
  • This gel is applied twice a day to acne-prone skin. After 6 to 12 weeks of treatment at a rate of 2 to 10 mg per cm 2 of treated skin and per application, there is a significant improvement.
  • An individual with psoriasis is given three tablets daily by mouth. After 30 days of treatment at a rate of 1 mg per kg of subject treated per day, there is a significant improvement.
  • the two gels are mixed immediately, weight for weight at the time of use.
  • This mixture is applied 2 times a day to acne-prone skin. After 4 to 6 weeks of treatment at a rate of 2 to 10 mg per cm 2 of treated skin and per application, there is a significant improvement.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Ophthalmology & Optometry (AREA)
  • Nutrition Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Claims (11)

  1. Stereospezifisches Retinoid-Derivat der Formel
    Figure imgb0083
     in welcher R für H oder einen C1-C4-Thioalkyl-Radikal steht.
  2. All-trans-Retinoid-Derivat nach Anspruch 1 der Formel
    Figure imgb0084
  3. 13-cis-Retinoid-Derivat nach Anspruch 1 der Formel
    Figure imgb0085
  4. All-trans-Retinoid-Derivat nach Anspruch 1 der Formel
    Figure imgb0086
  5. Verfahren zur Herstellung eines stereospezifischen Retinoids nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass man ein Dithianpropenal der Formel
    Figure imgb0087
     in welcher R dieselbe Bedeutung wie in Anspruch 1 hat, mit Ethyl-β-ionol der Formel
    Figure imgb0088
     in Anwesenheit eines Organomagnesiums reagieren lässt, so dass man die Acetylenverbindung der Formel
    Figure imgb0089
     erhält, in der R dieselbe Bedeutung wie oben hat, dann die Acetylenbindung der Verbindung der Formel (VIII) hydrogeniert, um das Diol der Formel
    Figure imgb0090
     zu erhalten, in der R dieselbe Bedeutung wie in Anspruch 1 hat, und dass man das Diol der Formel (V) mit Hilfe von Titan mit einer "niederen Wertigkeit" reduziert.
  6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, dass die Hogdrogenierung der Verbindung der Formel (VIII) mit Hilfe von Lithium- und Aluminiumhydrid durchgeführt wird.
  7. Kosmetische Zusammensetzung für die Körper- und Haarpflege, dadurch gekennzeichnet, dass sie in einem geeigneten kosmetischen Träger mindestens eine Verbindung nach einem der Ansprüche 1 bis 4 enthält.
  8. Zusammensetzung nach Anspruch 7, dadurch gekennzeichnet, dass sie, bezogen auf das Gesamtgewicht der Zusammensetzung, 0,001 bis etwa 3 Gew.-% mindestens einer Verbindung nach einem der Ansprüche 1 bis 4 enthält.
EP92401487A 1991-06-14 1992-06-01 Dithian substituierte Retinoide, ihre Verwendung, Verfahren zu ihrer Herstellung, diese enthaltende kosmetische und pharmazeutische Zusammensetzungen und ihre therapeutische Verwendung Expired - Lifetime EP0518722B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9107292 1991-06-14
FR9107292A FR2677650B1 (fr) 1991-06-14 1991-06-14 Retinouides substitues par un cycle dithiane et leur utilisation, procede de preparation desdits composes, compositions cosmetique et pharmaceutique les contenant et utilisation therapeutique de cette derniere.

Publications (2)

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EP0518722A1 EP0518722A1 (de) 1992-12-16
EP0518722B1 true EP0518722B1 (de) 1996-10-23

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EP92401487A Expired - Lifetime EP0518722B1 (de) 1991-06-14 1992-06-01 Dithian substituierte Retinoide, ihre Verwendung, Verfahren zu ihrer Herstellung, diese enthaltende kosmetische und pharmazeutische Zusammensetzungen und ihre therapeutische Verwendung

Country Status (8)

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US (1) US5296505A (de)
EP (1) EP0518722B1 (de)
JP (1) JP3184872B2 (de)
AT (1) ATE144507T1 (de)
CA (1) CA2070524C (de)
DE (1) DE69214728T2 (de)
ES (1) ES2093226T3 (de)
FR (1) FR2677650B1 (de)

Families Citing this family (5)

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Publication number Priority date Publication date Assignee Title
US6664287B2 (en) * 2000-03-15 2003-12-16 Bethesda Pharmaceuticals, Inc. Antioxidants
US6774100B2 (en) 2000-12-06 2004-08-10 Imaginative Research Associates, Inc. Anhydrous creams, lotions and gels
US20060189552A1 (en) * 2000-12-12 2006-08-24 Mohan Vishnupad Dispenser for dispensing three or more actives
US7060732B2 (en) * 2000-12-12 2006-06-13 Imaginative Research Associates, Inc. Antibiotic/benzoyl peroxide dispenser
US6462025B2 (en) 2000-12-12 2002-10-08 Imaginative Research Associates, Inc. Antibiotic/benzoyl peroxide dispenser

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2434136A1 (fr) * 1978-08-22 1980-03-21 Aec Chim Organ Biolog Nouvelles cetones ethyleniques, leur preparation et leur emploi
FR2615509B1 (fr) * 1987-05-21 1989-08-18 Oreal Procede de synthese de la vitamine a et de certains de ses derives
US5093360A (en) * 1989-04-07 1992-03-03 Yu Ruey J Retinal, derivatives and their therapeutic use

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US5296505A (en) 1994-03-22
DE69214728T2 (de) 1997-03-06
DE69214728D1 (de) 1996-11-28
JP3184872B2 (ja) 2001-07-09
CA2070524C (fr) 2003-05-20
EP0518722A1 (de) 1992-12-16
JPH05213933A (ja) 1993-08-24
FR2677650B1 (fr) 1993-09-24
ATE144507T1 (de) 1996-11-15
CA2070524A1 (fr) 1992-12-15
ES2093226T3 (es) 1996-12-16
FR2677650A1 (fr) 1992-12-18

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